Plasma kallikrein (KLKB1) (KLKB1)

Plasma kallikrein, encoded by the KLKB1 gene, is a serine protease synthesized primarily by hepatocytes and secreted into the blood as an inactive zymogen known as prekallikrein (UniProt, P03952). It is a central component of the kinin-kallikrein system, where it is activated by factor XIIa and subsequently cleaves high-molecular-weight kininogen (HMWK) to release bradykinin, a potent mediator of vascular permeability and inflammation (NCBI Gene, 3818). In patients with hereditary angioedema (HAE), the regulation of this pathway is impaired, leading to excessive bradykinin production and recurrent, life-threatening episodes of tissue swelling (PubMed, PMID: 32673570). Targeting the KLKB1 gene within hepatocyte DNA using CRISPR/Cas9 or other gene-editing technologies represents a transformative approach to HAE treatment. By permanently disrupting the gene at its primary site of production, these therapies aim to provide a durable reduction in systemic kallikrein levels, effectively preventing the inflammatory cascade and offering a potential functional cure for the disease (Intellia Therapeutics, 2024).

Other names

Plasma prekallikreinFletcher factorKininogeninPKPPK

Therapeutic strategies targeting KLKB1 involve either the direct inhibition of the plasma kallikrein enzyme's proteolytic activity or the reduction of its synthesis. Gene-editing therapies like NTLA-2002 utilize CRISPR/Cas9 to target the KLKB1 gene in hepatocyte DNA, creating permanent double-strand breaks that lead to gene knockout and a significant reduction in circulating prekallikrein levels (Intellia Therapeutics, 2024). Other modalities include antisense oligonucleotides (e.g., Donidalorsen) that promote the degradation of KLKB1 mRNA in the liver, and monoclonal antibodies or small molecules that bind to the active enzyme to prevent the cleavage of high-molecular-weight kininogen into bradykinin (PubMed, PMID: 33053314).